title: Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors.
abstract: Cancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O(2)(-). A high ratio of O(2)(-):H(2)O(2) oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O(2)(-) production and a reduced O(2)(-):H(2)O(2) ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhu
authors.forename: Ming Jie
authors.initials: MJ
authors.lastname: Tan
authors.forename: Royston-Luke
authors.initials: RL
authors.lastname: Huang
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.forename: Han Chung
authors.initials: HC
authors.lastname: Chong
authors.forename: Mintu
authors.initials: M
authors.lastname: Pal
authors.forename: Chee Ren Ivan
authors.initials: CR
authors.lastname: Lam
authors.forename: Petra
authors.initials: P
authors.lastname: Boukamp
authors.forename: Jiun Yit
authors.initials: JY
authors.lastname: Pan
authors.forename: Suat Hoon
authors.initials: SH
authors.lastname: Tan
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Hoi Yeung
authors.initials: HY
authors.lastname: Li
authors.forename: Jeak Ling
authors.initials: JL
authors.lastname: Ding
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D023102:Anoikis; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D015151:Immunoblotting; D016023:Integrins / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D016023:Integrins; D013481:Superoxides; D006861:Hydrogen Peroxide